scholarly journals Effects of Angiopoietin-Like 3 on Triglyceride Regulation, Glucose Homeostasis, and Diabetes

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Eliza Christopoulou ◽  
Moses Elisaf ◽  
Theodosios Filippatos
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
De Novo ◽  
Glucose Production ◽  
De Novo Lipogenesis ◽  
Metabolic Effects ◽  
Hepatic Insulin Resistance ◽  
Model Assessment ◽  
Loss Of Function

Angiopoietin-like 3 (ANGPTL3) is a regulator of plasma triglyceride (TRG) levels due to its inhibitory action on the activity of lipoprotein lipase (LPL). ANGPTL3 is proteolytically cleaved by proprotein convertases to generate an active N-terminal domain, which forms a complex with ANGPTL8 orchestrating LPL inhibition. ANGPTL3-4-8 mouse model studies indicate that these three ANGPTL family members play a significant role in partitioning the circulating TRG to specific tissues according to nutritional states. Recent data indicate a positive correlation of ANGPTL3 with plasma glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in insulin-resistant states. The aim of this review is to critically present the metabolic effects of ANGPTL3, focusing on the possible mechanisms involved in the dysregulation of carbohydrate homeostasis by this protein. Heterozygous and homozygous carriers of ANGPTL3 loss-of-function mutations have reduced risk for type 2 diabetes mellitus. Suggested mechanisms for the implication of ANGPTL3 in carbohydrate metabolism include the (i) increment of free fatty acids (FFAs) owing to the enhancement of lipolysis in adipose tissue, which can induce peripheral as well as hepatic insulin resistance; (ii) promotion of FFA flux to white adipose tissue during feeding, leading to the attenuation of de novo lipogenesis and decreased glucose uptake and insulin sensitivity; (iii) induction of hypothalamic LPL activity in mice, which is highly expressed throughout the brain and is associated with enhanced brain lipid sensing, reduction of food intake, and inhibition of glucose production (however, the effects of ANGPTL3 on hypothalamic LPL in humans need more clarification); and (iv) upregulation of ANGPTL4 expression (owing to the plasma FFA increase), which possibly enhances insulin resistance due to the selective inhibition of LPL in white adipose tissue leading to ectopic lipid accumulation and insulin resistance. Future trials will reveal if ANGPTL3 inhibition could be considered an alternative therapeutic target for dyslipidemia and dysglycemia.

scholarly journals Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms

2017 ◽  
Vol 114 (43) ◽  
pp. E9172-E9180 ◽  
Author(s):  
Giuseppe Ferrandino ◽  
Rachel R. Kaspari ◽  
Olga Spadaro ◽  
Andrea Reyna-Neyra ◽  
Rachel J. Perry ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
De Novo ◽  
Endogenous Glucose Production ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Down Regulation ◽  
Lipid Utilization ◽  
Adipose Tissue Lipolysis

Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.

scholarly journals Metabolic Effects of Oral Phenelzine Treatment on High-Sucrose-Drinking Mice

2018 ◽  
Vol 19 (10) ◽  
pp. 2904 ◽  
Author(s):  
Christian Carpéné ◽  
Saioa Gómez-Zorita ◽  
Alice Chaplin ◽  
Josep Mercader
Keyword(s):  
Adipose Tissue ◽  
Phosphoenolpyruvate Carboxykinase ◽  
De Novo ◽  
Uncoupling Protein ◽  
De Novo Lipogenesis ◽  
Metabolic Effects ◽  
Mrna Levels ◽  
Brown Adipose ◽  
High Sucrose ◽  
Sucrose Drinking

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.

scholarly journals Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

2020 ◽  
Author(s):  
Kasper W. ter Horst ◽  
Daniel F. Vatner ◽  
Dongyan Zhang ◽  
Gary W. Cline ◽  
Mariette T. Ackermans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bariatric Surgery ◽  
Liver Disease ◽  
Fatty Liver ◽  
Insulin Signaling ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

<b>Objective</b>: Both glucose and triglyceride production are increased in Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance, wherein insulin drives <i>de novo</i> lipogenesis (DNL), while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. <p><b>Research Design and Methods</b>: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-<sup>2</sup>H<sub>2</sub>]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (<sup>2</sup>H<sub>2</sub>O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery.</p> <p><b>Results</b>: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose <i>and</i> lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor <i>ChREBP</i> was increased in subjects with NAFLD. </p> <b>Conclusions</b>: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. <a></a>

scholarly journals Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kay H. M. Roumans ◽  
Lucas Lindeboom ◽  
Pandichelvam Veeraiah ◽  
Carlijn M. E. Remie ◽  
Esther Phielix ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
De Novo ◽  
Fatty Acid Fraction ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Acid Fraction

Effects of pregnancy and ovarian steroids on fatty acid synthesis and uptake in Syrian hamsters

1991 ◽  
Vol 260 (1) ◽  
pp. R153-R158 ◽  
Author(s):  
A. J. Bhatia ◽  
G. N. Wade
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
White Adipose Tissue ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Ovarian Steroids ◽  
Syrian Hamsters

The effects of pregnancy and ovarian steroids on the in vivo distribution of newly synthesized fatty acids (incorporation of tritium from 3H2O into fatty acid) in Syrian hamsters (Mesocricetus auratus) were examined. During late, but not early, gestation hamsters had reduced levels of newly synthesized fatty acids in heart, liver, uterus, and white adipose tissues (parametrial and inguinal fat pads). Treatment of ovariectomized hamsters with estradiol + progesterone significantly decreased fatty acid synthesis-uptake in heart, liver, and inguinal white adipose tissue. Treatment with either estradiol or progesterone alone was without significant effect in any tissue. Pretreatment of hamsters with Triton WR-1339 (tyloxapol), an inhibitor of lipoprotein lipase activity and tissue triglyceride uptake, abolished the effects of estradiol + progesterone in white adipose tissue and heart but not in liver. Thus hamsters lose body fat during pregnancy in part because of decreased de novo lipogenesis. The effect of pregnancy on lipogenesis is mimicked by treatment with estradiol + progesterone but not by either hormone alone. Furthermore, it appears that the liver is the principal site of estradiol + progesterone action on lipogenesis in Syrian hamsters.

scholarly journals Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men

2020 ◽  
Vol 21 (11) ◽  
pp. 4144 ◽  
Author(s):  
Pia Fahlbusch ◽  
Birgit Knebel ◽  
Tina Hörbelt ◽  
David Monteiro Barbosa ◽  
Aleksandra Nikolic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Energy Metabolism ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.

scholarly journals miR-146a regulates insulin sensitivity via NPR3

2020 ◽  
Author(s):  
Julian Roos ◽  
Meike Dahlhaus ◽  
Jan-Bernd Funcke ◽  
Monika Kustermann ◽  
Gudrun Strauss ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
De Novo ◽  
Liver Steatosis ◽  
De Novo Lipogenesis ◽  
Loss Of Function ◽  
High Fat

AbstractThe pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.

scholarly journals Human White Adipose Tissue Displays Selective Insulin Resistance in the Obese State

2021 ◽  
Author(s):  
Enrichetta Mileti ◽  
Kelvin HM. Kwok ◽  
Daniel P. Andersson ◽  
Anthony Mathelier ◽  
Amitha Raman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Insulin Response ◽  
Protein Translation ◽  
Hepatic Insulin Resistance ◽  
Post Surgery ◽  
Genes Encoding ◽  
Obese Subjects

Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of obese subjects and to what extent these are normalized by weight loss is unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and the insulin response in subcutaneous WAT by RNA-sequencing in 23 women with obesity before and two years after bariatric surgery. To control for effects of surgery, women post-surgery were matched to never-obese subjects. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a <i>common</i> set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of <i>obesity-attenuated</i> genes linked to tissue remodelling and protein translation was selectively regulated in the two non-obese states and several <i>post obesity-enriched</i> genes encoding proteins involved in e.g. one carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether,<b> </b>human WAT displays a selective insulin response in the obese state where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.

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